Host cysteine proteases promote the severity of catheter-associated urinary tract infection and kidney fibrosis
Abstract
ABSTRACT The bacterium Enterococcus faecalis is a leading cause of catheter-associated urinary tract infection (CAUTI), whose treatment is increasingly challenged by antibiotic resistance. In examining alternative therapies, we previously found that the cysteine protease inhibitor E64 dramatically reduced bladder inflammation and bacterial dissemination in a murine model of E. faecalis CAUTI. However, the role of cysteine proteases in pathogenesis and the target(s) of E64 are unknown. Here, we found that while it did not affect E. faecalis growth in vitro, in a murine CAUTI model, E64 reduced host caspase-1-dependent cellular apoptosis and necrosis, levels of several pro-inflammatory cytokines, bladder epithelial damage, and formation of renal abscesses. Analysis of host cell transcription and inflammatory cell populations revealed that E64 did not affect neutrophil numbers but did enhance the expression of C-C chemokine receptor type 3 (CCR3), a receptor for eosinophil-specific chemokines, with a concomitant increase in eosinophil numbers. Treatments that reduced or increased the eosinophil response (anti-interleukin 5 antibody or eotaxin, respectively) confirmed a role for eosinophils in controlling bacterial burdens. Analysis of a panel of host cysteine proteases in vivo demonstrated that E64 decreased the activation of cathepsin L; subsequently, we found that the infection of cathepsin L-deficient mice yielded lower catheter and bladder colonization compared to wild-type…
Read the paper
Related studies
- Association of lower urinary tract symptoms and OAB severity with quality of life and mental health in China, Taiwan and South Korea: results from a cross-sectional, population-based study
- Ten-Day Quadruple Therapy Comprising Low-Dose Rabeprazole, Bismuth, Amoxicillin, and Tetracycline Is an Effective and Safe First-Line Treatment for Helicobacter pylori Infection in a Population with High Antibiotic Resistance: a Prospective, Multicenter, Randomized, Parallel-Controlled Clinical Trial in China
- The Role of the NLR and PLR in Urinary Tract Infection
- Threat of Antimicrobial Resistance among Pilgrims with Infectious Diseases during Hajj: Lessons Learnt from COVID-19 Pandemic
- Leclercia adecarboxylata urinary tract infection in a patient with bladder cancer and recurrent hematuria
- A Case Series of Staphylococcus lugdunensis Infection in Cancer Patients at an Academic Cancer Institute in the United States
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.